Thiazolidinedione analogues for the treatment of metabolic diseases

ABSTRACT

The present invention relates to thiazolidinedione analogues that are useful for treating hypertension, diabetes, and inflammatory diseases. Formula (I), wherein: each of R 1  and R 4  is independently selected from H, halo, aliphatic, and alkoxy, wherein the aliphatic and alkoxy are optionally substituted with 1-3 of halo; R 2  is halo, hydroxy, or optionally substituted aliphatic, and R′ 2  is H, or R 2  and R′ 2  together form oxo; R 3  is H; and Ring A is a phenyl.

CLAIM OF PRIORITY

This application claims the priority of U.S. Provisional Application No.60/972,639 filed on Sep. 14, 2007, the entire contents of which isincorporated herein.

TECHNICAL FIELD OF THE INVENTION

The present invention provides a pharmaceutical composition thatincludes selective thiazolidinedione analogs for use in treating andpreventing diabetes, hypertension, diabetes, and inflammatory diseasesand inflammatory diseases.

BACKGROUND OF THE INVENTION

Over the past several decades, scientists have postulated that PPARγ isthe generally accepted site of action for insulin sensitizingthiazolidinedione compounds.

Peroxisome Proliferator Activated Receptors (PPARs) are members of thenuclear hormone receptor super family, which are ligand-activatedtranscription factors regulating gene expression. PPARs have beenimplicated in autoimmune diseases and other diseases, i.e diabetesmellitus, cardiovascular and gastrointestinal disease, and Alzheimer'sdisease.

PPARγ is a key regulator of adipocyte differentiation and lipidmetabolism. PPARγ is also found in other cell types includingfibroblasts, myocytes, breast cells, human bone-marrow precursors, andmacrophages/monocytes. In addition, PPARγ has been shown in macrophagefoam cells in atherosclerotic plaques.

Thiazolidinediones, developed originally for the treatment of type-2diabetes, generally exhibit high-affinity as PPARγ ligands. The findingthat thiazolidinediones might mediate their therapeutic effects throughdirect interactions with PPARγ helped to establish the concept thatPPARγ is a key regulator of glucose and lipid homeostasis. However,compounds that involve the activation of PPARγ also trigger sodiumreabsorption and other unpleasant side effects.

SUMMARY OF THE INVENTION

In general, the invention relates to compounds that have reduced bindingand activation of the nuclear transcription factor PPARγ. Compoundsexhibiting PPARγ activity induce transcription of genes that favorsodium re-adsorption. The compounds of this invention have reducedbinding or activation of the nuclear transcription factor PPARγ, do notaugment sodium re-absorption, and are therefore more useful in treatinghypertension, diabetes, and inflammatory diseases. Advantageously, thecompounds having lower PPARγ activity exhibit fewer side effects thancompounds having higher levels of PPARγ activity. Most specifically, bylacking PPARγ binding and activation activity these compounds areparticularly useful for treating hypertension, diabetes, andinflammatory diseases both as single agents and in combination withother classes of antihypertensive agents. As hypertension, diabetes, andinflammatory diseases is a major risk factor in diabetes andprediabetes, these compounds are also useful for the treatment andprevention of diabetes and other inflammatory diseases.

In one aspect, the present invention provides a pharmaceuticalcomposition useful in treating hypertension, diabetes, and inflammatorydiseases comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Each of R₁ and R₄ is independently selected from H, halo, aliphatic, andalkoxy, wherein the aliphatic and alkoxy are optionally substituted with1-3 of halo;

R₂ is halo, hydroxy, or optionally substituted aliphatic, and R′₂ is H,or R₂ and R′₂ together form oxo;

R₃ is H; and

Ring A is phenyl.

Another aspect of the present invention provides methods of treatinghypertension, diabetes, and inflammatory diseases with a pharmaceuticalcomposition comprising a compound of formula I and a pharmaceuticallyacceptable carrier.

Another aspect of this invention provides pharmaceutical compositionscomprising a compound of formula I and at least one diuretic, such ashydrocholothiazide. Other aspects provide pharmaceutical compositionsuseful for treating hypertension, diabetes, and inflammatory diseasescomprising a compound of formula I and one or more agents that limit theactivity of the renin-angiotensin system such as angiotensin concertingenzyme inhibitors, i.e. ACE inhibitors, e.g. ramipril, captopril,enalapril, or the like, and/or angiotensin II receptor blockers, i.e.ARBs, e.g. candesartan, losartan, olmesartan, or the like; and/or renininhibitors. Still other aspects provide a useful pharmaceuticalcomposition for treating hypertension, diabetes, and inflammatorydiseases comprising a compound of formula I and compounds that limithypertension, by alternate means including β-adrenergic receptorblockers and calcium channel blockers, e.g., amlodipine.

This invention also provides pharmaceutical combinations containing acompound of formula I and a lipid lowering agent. Compounds of formulaI, because of their PPARγ-sparing properties and beneficial effects onlipids to lower triglycerides and elevate HDL cholesterol, areparticularly useful in combination with one or more statin, i.e.,HMG-CoA reductase inhibitor, e.g., atorvastatin, cerivastatin,fluvastatin, lovastatin, mevastatin, simvastatin, rosuvastatin,pravastatin, or any pharmaceutically acceptable combination thereof.

In another aspect, the invention relates to insulin sensitizers thathave reduced binding and activation of the nuclear transcription factorPPARγ and therefore produce reduced sodium re-absorption and fewerdose-limiting side effects. Thus, the compounds of formula I aresubstantially more effective to treat and prevent diabetes and othermetabolic inflammation mediated diseases including all aspects ofinsulin resistance associated with metabolic syndrome includingdyslipidemia and central obesity. The compounds of formula I are alsouseful for treating other inflammatory diseases such as rheumatoidarthritis, lupus, myasthenia gravis, vasculitis, Chronic ObstructivePulmonary Disease (COPD), and inflammatory bowel disease as well asneurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease, multiple schlerosis, acute allergic reactions, transplantrejections, central obesity, dyslipidemia, prediabetes and diabetes.

In another aspect, the present invention provides pharmaceuticalcompositions comprising a compound of formula I and metformin.

In still another aspect, the invention provides pharmaceuticalcompositions comprising a compound of formula I, a second agent, apharmaceutically acceptable carrier, wherein the second agent isselected from dipeptidyl peptidase IV, i.e., DPP-4, inhibitors, e.g.,sitagliptin, vildagliptin, or the like; statins, i.e., HMG-CoA reductaseinhibitor, e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin,mevastatin, simvastatin, rosuvastatin, pravastatin, or anypharmaceutically acceptable combination thereof; GLP-1 and -2 agonists;or combinations thereof.

In still another aspect, the invention provides a combination ofcompound of formula I and a glucocorticoid agonist which is useful fortreating a number of inflammatory diseases and conditions includingtherapies of suppressing the immune response, preventing transplantrejections, and treating autoimmune diseases. Exemplary diseases andconditions, include rheumatoid arthritis, lupus, myasthenia gravis,muscular dystrophy vasculitis, multiple schlerosis, Chronic ObstructivePulmonary Disease (COPD), inflammatory bowel disease, treatment of acuteallergic reactions, and transplant rejection.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the following definitions shall apply unless otherwiseindicated.

I. Definitions

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75th Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry”,Thomas Sorrell, University Science Books, Sausalito: 1999, and “March'sAdvanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. and March, J.,John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention.

As used herein, the term “glucocorticoid agonist” refers to steroidhormones characterized by their ability to bind with the cortisolreceptor. Examples of glucocorticoid agonists include, but are notlimited to, Hydrocortisone, Cortisone acetate, Prednisone, Prednisolone,Methylprednisolone, Dexamethasone, Betamethasone, Triamcinolone,Beclometasone, Fludrocortisone acetate, Deoxycorticosterone acetate(DOCA), and Aldosterone.

As used herein the term “aliphatic” encompasses the terms alkyl,alkenyl, alkynyl, each of which being optionally substituted as setforth below.

As used herein, an “alkyl” group refers to a saturated aliphatichydrocarbon group containing 1-12 (e.g., 1-8, 1-6, or 1-4) carbon atoms.An alkyl group can be straight or branched. Examples of alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or2-ethylhexyl. An alkyl group can be substituted (i.e., optionallysubstituted) with one or more substituents such as halo, phospho,cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic[e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl,alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl,(cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro,cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino,aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino,heteroaralkylcarbonylamino alkylaminocarbonyl, cycloalkylaminocarbonyl,heterocycloalkylaminocarbonyl, arylaminocarbonyl, orheteroarylaminocarbonyl], amino [e.g., aliphaticamino,cycloaliphaticamino, or heterocycloaliphaticamino], sulfonyl [e.g.,aliphatic-SO₂-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl,sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy,heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy,heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. Withoutlimitation, some examples of substituted alkyls include carboxyalkyl(such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl),cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl,(alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as(alkyl-SO₂-amino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl,or haloalkyl.

As used herein, an “alkenyl” group refers to an aliphatic carbon groupthat contains 2-8 (e.g., 2-12, 2-6, or 2-4) carbon atoms and at leastone double bond. Like an alkyl group, an alkenyl group can be straightor branched. Examples of an alkenyl group include, but are not limitedto allyl, isoprenyl, 2-butenyl, and 2-hexenyl. An alkenyl group can beoptionally substituted with one or more substituents such as halo,phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl],heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl],aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g.,(aliphatic)carbonyl, (cycloaliphatic)carbonyl, or(heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g.,(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino alkylaminocarbonyl,cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g.,aliphaticamino, cycloaliphaticamino, heterocycloaliphaticamino, oraliphaticsulfonylamino], sulfonyl [e.g., alkyl-SO₂—,cycloaliphatic-SO₂—, or aryl-SO₂—], sulfinyl, sulfanyl, sulfoxy, urea,thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl,cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy,aralkyloxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyloxy, orhydroxy. Without limitation, some examples of substituted alkenylsinclude cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl,aralkenyl, (alkoxyaryl)alkenyl, (sulfonylamino)alkenyl (such as(alkyl-SO₂-amino)alkenyl), aminoalkenyl, amidoalkenyl,(cycloaliphatic)alkenyl, or haloalkenyl.

As used herein, an “alkynyl” group refers to an aliphatic carbon groupthat contains 2-8 (e.g., 2-12, 2-6, or 2-4) carbon atoms and has atleast one triple bond. An alkynyl group can be straight or branched.Examples of an alkynyl group include, but are not limited to, propargyland butynyl. An alkynyl group can be optionally substituted with one ormore substituents such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy,heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy,cyano, halo, hydroxy, sulfo, mercapto, sulfanyl [e.g., aliphaticsulfanylor cycloaliphaticsulfanyl], sulfinyl [e.g., aliphaticsulfinyl orcycloaliphaticsulfinyl], sulfonyl [e.g., aliphatic-SO₂—,aliphaticamino-SO₂—, or cycloaliphatic-SO₂—], amido [e.g.,aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino,cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino,aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,(cycloalkylalkyl)carbonylamino, heteroaralkylcarbonylamino,heteroarylcarbonylamino or heteroarylaminocarbonyl], urea, thiourea,sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic,heterocycloaliphatic, aryl, heteroaryl, acyl [e.g.,(cycloaliphatic)carbonyl or (heterocycloaliphatic)carbonyl], amino[e.g., aliphaticamino], sulfoxy, oxo, carboxy, carbamoyl,(cycloaliphatic)oxy, (heterocycloaliphatic)oxy, or (heteroaryl)alkoxy.

As used herein, an “amido” encompasses both “aminocarbonyl” and“carbonylamino”. These terms when used alone or in connection withanother group refer to an amido group such as —N(R^(X))—C(O)—R^(Y) or—C(O)—N(R^(X))₂, when used terminally, and —C(O)—N(R^(X))— or—N(R^(X))—C(O)— when used internally, wherein R^(X) and R^(Y) aredefined below. Examples of amido groups include alkylamido (such asalkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic)amido,(heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido,arylamido, aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido.

As used herein, an “amino” group refers to —NR^(X)R^(Y) wherein each ofR^(X) and R^(Y) is independently hydrogen, aliphatic, cycloaliphatic,(cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic,(heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl,sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl,((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl,(araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or(heteroaraliphatic)carbonyl, each of which being defined herein andbeing optionally substituted. Examples of amino groups includealkylamino, dialkylamino, or arylamino. When the term “amino” is not theterminal group (e.g., alkylcarbonylamino), it is represented by—NR^(X)—. R^(X) has the same meaning as defined above.

As used herein, an “aryl” group used alone or as part of a larger moietyas in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” refers to monocyclic(e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl,tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyltetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systemsin which the monocyclic ring system is aromatic or at least one of therings in a bicyclic or tricyclic ring system is aromatic. The bicyclicand tricyclic groups include benzofused 2-3 membered carbocyclic rings.For example, a benzofused group includes phenyl fused with two or moreC₄₋₈ carbocyclic moieties. An aryl is optionally substituted with one ormore substituents including aliphatic [e.g., alkyl, alkenyl, oralkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic;heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl;alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy;heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl;heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring of abenzofused bicyclic or tricyclic aryl); nitro; carboxy; amido; acyl[e.g., (aliphatic)carbonyl; (cycloaliphatic)carbonyl;((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl;(heterocycloaliphatic)carbonyl;((heterocycloaliphatic)aliphatic)carbonyl; or(heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphatic-SO₂— oramino-SO₂—]; sulfinyl [e.g., aliphatic-S(O)— or cycloaliphatic-S(O)-];sulfanyl [e.g., aliphatic-S-]; cyano; halo; hydroxy; mercapto; sulfoxy;urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, anaryl can be unsubstituted.

Non-limiting examples of substituted aryls include haloaryl [e.g.,mono-, di (such as p,m-dihaloaryl), and (trihalo)aryl]; (carboxy)aryl[e.g., (alkoxycarbonyl)aryl, ((aralkyl)carbonyloxy)aryl, and(alkoxycarbonyl)aryl]; (amido)aryl [e.g., (aminocarbonyl)aryl,(((alkylamino)alkyl)aminocarbonyl)aryl, (alkylcarbonyl)aminoaryl,(arylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyl)aryl];aminoaryl [e.g., ((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl];(cyanoalkyl)aryl; (alkoxy)aryl; (sulfamoyl)aryl [e.g.,(aminosulfonyl)aryl]; (alkylsulfonyl)aryl; (cyano)aryl;(hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl,((carboxy)alkyl)aryl; (((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl;(((alkylsulfonyl)amino)alkyl)aryl; ((heterocycloaliphatic)carbonyl)aryl;((alkylsulfonyl)alkyl)aryl; (cyanoalkyl)aryl; (hydroxyalkyl)aryl;(alkylcarbonyl)aryl; alkylaryl; (trihaloalkyl)aryl;p-amino-m-alkoxycarbonylaryl; p-amino-m-cyanoaryl; p-halo-m-aminoaryl;or (m-(heterocycloaliphatic)-o-(alkyl))aryl.

As used herein, an “araliphatic” such as an “aralkyl” group refers to analiphatic group (e.g., a C₁₋₄ alkyl group) that is substituted with anaryl group. “Aliphatic,” “alkyl,” and “aryl” are defined herein. Anexample of an araliphatic such as an aralkyl group is benzyl.

As used herein, an “aralkyl” group refers to an alkyl group (e.g., aC₁₋₄ alkyl group) that is substituted with an aryl group. Both “alkyl”and “aryl” have been defined above. An example of an aralkyl group isbenzyl. An aralkyl is optionally substituted with one or moresubstituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl,including carboxyalkyl, hydroxyalkyl, or haloalkyl such astrifluoromethyl], cycloaliphatic [e.g., cycloalkyl or cycloalkenyl],(cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl,heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy,heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro,carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [e.g., aminocarbonyl,alkylcarbonylamino, cycloalkylcarbonylamino,(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, or heteroaralkylcarbonylamino], cyano, halo,hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, or carbamoyl.

As used herein, a “bicyclic ring system” includes 8-12 (e.g., 9, 10, or11) membered structures that form two rings, wherein the two rings haveat least one atom in common (e.g., 2 atoms in common). Bicyclic ringsystems include bicycloaliphatics (e.g., bicycloalkyl orbicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and bicyclicheteroaryls.

As used herein, a “cycloaliphatic” group encompasses a “cycloalkyl”group and a “cycloalkenyl” group, each of which being optionallysubstituted as set forth below.

As used herein, a “cycloalkyl” group refers to a saturated carbocyclicmono- or bicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbonatoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl,octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl,bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl,bicyclo[2.2.2]octyl, adamantyl, or((aminocarbonyl)cycloalkyl)cycloalkyl.

A “cycloalkenyl” group, as used herein, refers to a non-aromaticcarbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or moredouble bonds. Examples of cycloalkenyl groups include cyclopentenyl,1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl,octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo[2.2.2]octenyl,or bicyclo[3.3.1]nonenyl.

A cycloalkyl or cycloalkenyl group can be optionally substituted withone or more substituents such as phosphor, aliphatic [e.g., alkyl,alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic) aliphatic,heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl,heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy,aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl,heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino,(cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino,(aryl)carbonylamino, (araliphatic)carbonylamino,(heterocycloaliphatic)carbonylamino,((heterocycloaliphatic)aliphatic)carbonylamino,(heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro,carboxy [e.g., HOOC—, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g.,(cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl,(araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,((heterocycloaliphatic)aliphatic)carbonyl, or(heteroaraliphatic)carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl[e.g., alkyl-SO₂— and aryl-SO₂—], sulfinyl [e.g., alkyl-S(O)-], sulfanyl[e.g., alkyl-S-], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, orcarbamoyl.

As used herein, the term “heterocycloaliphatic” encompasses aheterocycloalkyl group and a heterocycloalkenyl group, each of whichbeing optionally substituted as set forth below.

As used herein, a “heterocycloalkyl” group refers to a 3-10 memberedmono- or bicylic (fused or bridged) (e.g., 5- to 10-membered mono- orbicyclic) saturated ring structure, in which one or more of the ringatoms is a heteroatom (e.g., N, O, S, or combinations thereof). Examplesof a heterocycloalkyl group include piperidyl, piperazyl,tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl,1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl,octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl,octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl,octahydrobenzo[b]thiophenyl, 2-oxa-bicyclo[2.2.2]octyl,1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and2,6-dioxa-tricyclo[3.3.1.0^(3,7)]nonyl. A monocyclic heterocycloalkylgroup can be fused with a phenyl moiety to form structures, such astetrahydroisoquinoline, which would be categorized as heteroaryls.

A “heterocycloalkenyl” group, as used herein, refers to a mono- orbicylic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ringstructure having one or more double bonds, and wherein one or more ofthe ring atoms is a heteroatom (e.g., N, O, or S). Monocyclic andbicyclic heterocycloaliphatics are numbered according to standardchemical nomenclature.

A heterocycloalkyl or heterocycloalkenyl group can be optionallysubstituted with one or more substituents such as phosphor, aliphatic[e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic,(cycloaliphatic)aliphatic, heterocycloaliphatic,(heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy,(cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy,(araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino,amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino,((cycloaliphatic) aliphatic)carbonylamino, (aryl)carbonylamino,(araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino,((heterocycloaliphatic) aliphatic)carbonylamino,(heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro,carboxy [e.g., HOOC—, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g.,(cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl,(araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,((heterocycloaliphatic)aliphatic)carbonyl, or(heteroaraliphatic)carbonyl], nitro, cyano, halo, hydroxy, mercapto,sulfonyl [e.g., alkylsulfonyl or arylsulfonyl], sulfinyl [e.g.,alkylsulfinyl], sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, or carbamoyl.

A “heteroaryl” group, as used herein, refers to a monocyclic, bicyclic,or tricyclic ring system having 4 to 15 ring atoms wherein one or moreof the ring atoms is a heteroatom (e.g., N, O, S, or combinationsthereof) and in which the monocyclic ring system is aromatic or at leastone of the rings in the bicyclic or tricyclic ring systems is aromatic.A heteroaryl group includes a benzofused ring system having 2 to 3rings. For example, a benzofused group includes benzo fused with one ortwo 4 to 8 membered heterocycloaliphatic moieties (e.g., indolizyl,indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, quinolinyl, or isoquinolinyl). Some examples ofheteroaryl are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl,thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl,isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine,dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl,indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl,quinazolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl,4H-quinolizyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl.

Without limitation, monocyclic heteroaryls include furyl, thiophenyl,2H-pyrrolyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl,pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl.Monocyclic heteroaryls are numbered according to standard chemicalnomenclature.

Without limitation, bicyclic heteroaryls include indolizyl, indolyl,isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl,quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indolyl,benzo[b]furyl, bexo[b]thiophenyl, indazolyl, benzimidazyl,benzthiazolyl, purinyl,

4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl,quinoxalyl, 1,8-naphthyridyl, or pteridyl. Bicyclic heteroaryls arenumbered according to standard chemical nomenclature.

A heteroaryl is optionally substituted with one or more substituentssuch as aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic;(cycloaliphatic)aliphatic; heterocycloaliphatic;(heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy;(cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy;(araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo(on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic ortricyclic heteroaryl); carboxy; amido; acyl [e.g., aliphaticcarbonyl;(cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl;(araliphatic)carbonyl; (heterocycloaliphatic)carbonyl;((heterocycloaliphatic)aliphatic)carbonyl; or(heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphaticsulfonyl oraminosulfonyl]; sulfinyl [e.g., aliphaticsulfinyl]; sulfanyl [e.g.,aliphaticsulfanyl]; nitro; cyano; halo; hydroxy; mercapto; sulfoxy;urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, aheteroaryl can be unsubstituted.

Non-limiting examples of substituted heteroaryls include(halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl];(carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroaryl]; cyanoheteroaryl;aminoheteroaryl [e.g., ((alkylsulfonyl)amino)heteroaryl and((dialkyl)amino)heteroaryl]; (amido)heteroaryl [e.g.,aminocarbonylheteroaryl, ((alkylcarbonyl)amino)heteroaryl,((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl,(((heteroaryl)amino)carbonyl)heteroaryl,((heterocycloaliphatic)carbonyl)heteroaryl, and((alkylcarbonyl)amino)heteroaryl]; (cyanoalkyl)heteroaryl;(alkoxy)heteroaryl; (sulfamoyl)heteroaryl [e.g.,(aminosulfonyl)heteroaryl]; (sulfonyl)heteroaryl [e.g.,(alkylsulfonyl)heteroaryl]; (hydroxyalkyl)heteroaryl;(alkoxyalkyl)heteroaryl; (hydroxy)heteroaryl;((carboxy)alkyl)heteroaryl; (((dialkyl)amino)alkyl]heteroaryl;(heterocycloaliphatic)heteroaryl; (cycloaliphatic)heteroaryl;(nitroalkyl)heteroaryl; (((alkylsulfonyl)amino)alkyl)heteroaryl;((alkylsulfonyl)alkyl)heteroaryl; (cyanoalkyl)heteroaryl;(acyl)heteroaryl [e.g., (alkylcarbonyl)heteroaryl]; (alkyl)heteroaryl,and (haloalkyl)heteroaryl [e.g., trihaloalkylheteroaryl].

A “heteroaraliphatic (such as a heteroaralkyl group) as used herein,refers to an aliphatic group (e.g., a C₁₋₄ alkyl group) that issubstituted with a heteroaryl group. “Aliphatic,” “alkyl,” and“heteroaryl” have been defined above.

A “heteroaralkyl” group, as used herein, refers to an alkyl group (e.g.,a C₁₋₄ alkyl group) that is substituted with a heteroaryl group. Both“alkyl” and “heteroaryl” have been defined above. A heteroaralkyl isoptionally substituted with one or more substituents such as alkyl(including carboxyalkyl, hydroxyalkyl, and haloalkyl such astrifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy,cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl,alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino,cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino,arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo,hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, or carbamoyl.

As used herein, “cyclic moiety” and “cyclic group” refer to mono-, bi-,and tri-cyclic ring systems including cycloaliphatic,heterocycloaliphatic, aryl, or heteroaryl, each of which has beenpreviously defined.

As used herein, a “bridged bicyclic ring system” refers to a bicyclicheterocyclicalipahtic ring system or bicyclic cycloaliphatic ring systemin which the rings are bridged. Examples of bridged bicyclic ringsystems include, but are not limited to, adamantanyl, norbornanyl,bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl,bicyclo[3.2.3]nonyl, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl,3-azabicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.0^(3,7)]nonyl. Abridged bicyclic ring system can be optionally substituted with one ormore substituents such as alkyl (including carboxyalkyl, hydroxyalkyl,and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl,heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy,heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro,carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl,alkylcarbonylamino, cycloalkylcarbonylamino,(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo,hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, or carbamoyl.

As used herein, an “acyl” group refers to a formyl group or R^(X)—C(O)—(such as alkyl-C(O)—, also referred to as “alkylcarbonyl”) where R^(X)and “alkyl” have been defined previously. Acetyl and pivaloyl areexamples of acyl groups.

As used herein, an “aroyl” or “heteroaroyl” refers to an aryl-C(O)— or aheteroaryl-C(O)—. The aryl and heteroaryl portion of the aroyl orheteroaroyl is optionally substituted as previously defined.

As used herein, an “alkoxy” group refers to an alkyl-O— group where“alkyl” has been defined previously.

As used herein, a “carbamoyl” group refers to a group having thestructure —O—CO—NR^(X)R^(Y) or —NR^(X)—CO—O—R^(Z), wherein R^(X) andR^(Y) have been defined above and R^(Z) can be aliphatic, aryl,araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic.

As used herein, a “carboxy” group refers to —COOH, —COOR^(X), —OC(O)H,—OC(O)R^(X), when used as a terminal group; or —OC(O)— or —C(O)O— whenused as an internal group.

As used herein, a “haloaliphatic” group refers to an aliphatic groupsubstituted with 1-3 halogen. For instance, the term haloalkyl includesthe group —CF₃.

As used herein, a “mercapto” group refers to —SH.

As used herein, a “sulfo” group refers to —SO₃H or —SO₃R^(X) when usedterminally or —S(O)₃— when used internally.

As used herein, a “sulfamide” group refers to the structure—NR^(X)—S(O)₂—NR^(Y)R^(Z) when used terminally and —NR^(X)—S(O)₂—NR^(Y)—when used internally, wherein R^(X), R^(Y), and R^(Z) have been definedabove.

As used herein, a “sulfonamide” group refers to the structure—S(O)₂—NR^(X)R^(Y) or —NR^(X)—S(O)₂—R^(Z) when used terminally; or—S(O)₂—NR^(X)— or —NR^(X)—S(O)₂— when used internally, wherein R^(X),R^(Y), and R^(Z) are defined above.

As used herein a “sulfanyl” group refers to —S—R^(X) when usedterminally and —S— when used internally, wherein R^(X) has been definedabove. Examples of sulfanyls include aliphatic-S—, cycloaliphatic-S—,aryl-S—, or the like.

As used herein a “sulfinyl” group refers to —S(O)—R^(X) when usedterminally and —S(O)— when used internally, wherein R^(X) has beendefined above. Exemplary sulfinyl groups include aliphatic-S(O)—,aryl-S(O)—, (cycloaliphatic(aliphatic))-S(O)—, cycloalkyl-S(O)—,heterocycloaliphatic-S(O)—, heteroaryl-S(O)—, or the like.

As used herein, a “sulfonyl” group refers to —S(O)₂—R^(X) when usedterminally and —S(O)₂— when used internally, wherein R^(X) has beendefined above. Exemplary sulfonyl groups include aliphatic-S(O)₂—,aryl-S(O)₂—, (cycloaliphatic(aliphatic))-S(O)₂—, cycloaliphatic-S(O)₂—,heterocycloaliphatic-S(O)₂—, heteroaryl-S(O)₂—,(cycloaliphatic(amido(aliphatic)))-S(O)₂— or the like.

As used herein, a “sulfoxy” group refers to —O—SO—R^(X) or —SO—O—R^(X),when used terminally and —O—S(O)— or —S(O)—O— when used internally,where R^(X) has been defined above.

As used herein, a “halogen” or “halo” group refers to fluorine,chlorine, bromine or iodine.

As used herein, an “alkoxycarbonyl,” which is encompassed by the termcarboxy, used alone or in connection with another group refers to agroup such as alkyl-O—C(O)—.

As used herein, an “alkoxyalkyl” refers to an alkyl group such asalkyl-O-alkyl-, wherein alkyl has been defined above.

As used herein, a “carbonyl” refer to —C(O)—.

As used herein, an “oxo” refers to ═O.

As used herein, the term “phospho” refers to phosphinates andphosphonates. Examples of phosphinates and phosphonates include—P(O)(R^(P))₂, wherein R^(P) is aliphatic, alkoxy, aryloxy,heteroaryloxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy aryl,heteroaryl, cycloaliphatic or amino.

As used herein, an “aminoalkyl” refers to the structure(R^(X))₂N-alkyl-.

As used herein, a “cyanoalkyl” refers to the structure (NC)-alkyl-.

As used herein, a “urea” group refers to the structure—NR^(X)—CO—NR^(Y)R^(Z) and a “thiourea” group refers to the structure—NR^(X)—CS—NR^(Y)R^(Z) when used terminally and —NR^(X)—CO—NR^(Y)— or—NR^(X)—CS—NR^(Y)— when used internally, wherein Rx, R^(Y), and R^(Z)have been defined above.

As used herein, a “guanidine” group refers to the structure—N═C(N(R^(X)R^(Y)))N(R^(X)R^(Y)) or —NR^(X)—C(═NR^(X))NR^(X)R^(Y)wherein R^(X) and R^(Y) have been defined above.

As used herein, the term “amidino” group refers to the structure—C═(NR^(X))N(R^(X)R^(Y)) wherein R^(X) and R^(Y) have been definedabove.

In general, the term “vicinal” refers to the placement of substituentson a group that includes two or more carbon atoms, wherein thesubstituents are attached to adjacent carbon atoms.

In general, the term “geminal” refers to the placement of substituentson a group that includes two or more carbon atoms, wherein thesubstituents are attached to the same carbon atom.

The terms “terminally” and “internally” refer to the location of a groupwithin a substituent. A group is terminal when the group is present atthe end of the substituent not further bonded to the rest of thechemical structure. Carboxyalkyl, i.e., R^(X)O(O)C-alkyl is an exampleof a carboxy group used terminally. A group is internal when the groupis present in the middle of a substituent of the chemical structure.Alkylcarboxy (e.g., alkyl-C(O)O— or alkyl-OC(O)—) and alkylcarboxyaryl(e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxygroups used internally.

As used herein, an “aliphatic chain” refers to a branched or straightaliphatic group (e.g., alkyl groups, alkenyl groups, or alkynyl groups).A straight aliphatic chain has the structure

—[CH₂]_(v)—, where v is 1-12. A branched aliphatic chain is a straightaliphatic chain that is substituted with one or more aliphatic groups. Abranched aliphatic chain has the structure —[CQQ]_(v)- where Q isindependently a hydrogen or an aliphatic group; however, Q shall be analiphatic group in at least one instance. The term aliphatic chainincludes alkyl chains, alkenyl chains, and alkynyl chains, where alkyl,alkenyl, and alkynyl are defined above.

The phrase “optionally substituted” is used interchangeably with thephrase “substituted or unsubstituted.” As described herein, compounds ofthe invention can optionally be substituted with one or moresubstituents, such as are illustrated generally above, or as exemplifiedby particular classes, subclasses, and species of the invention. Asdescribed herein, the variables R₁, R₂, and R₃, and other variablescontained in formulae described herein encompass specific groups, suchas alkyl and aryl. Unless otherwise noted, each of the specific groupsfor the variables R₁, R₂, and R₃, and other variables contained thereincan be optionally substituted with one or more substituents describedherein. Each substituent of a specific group is further optionallysubstituted with one to three of halo, cyano, oxo, alkoxy, hydroxy,amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic, heteroaryl,haloalkyl, and alkyl. For instance, an alkyl group can be substitutedwith alkylsulfanyl and the alkylsulfanyl can be optionally substitutedwith one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro,aryl, haloalkyl, and alkyl. As an additional example, the cycloalkylportion of a (cycloalkyl)carbonylamino can be optionally substitutedwith one to three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, andalkyl. When two alkoxy groups are bound to the same atom or adjacentatoms, the two alkoxy groups can form a ring together with the atom(s)to which they are bound.

In general, the term “substituted,” whether preceded by the term“optionally” or not, refers to the replacement of hydrogen radicals in agiven structure with the radical of a specified substituent. Specificsubstituents are described above in the definitions and below in thedescription of compounds and examples thereof. Unless otherwiseindicated, an optionally substituted group can have a substituent ateach substitutable position of the group, and when more than oneposition in any given structure can be substituted with more than onesubstituent selected from a specified group, the substituent can beeither the same or different at every position. A ring substituent, suchas a heterocycloalkyl, can be bound to another ring, such as acycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings shareone common atom. As one of ordinary skill in the art will recognize,combinations of substituents envisioned by this invention are thosecombinations that result in the formation of stable or chemicallyfeasible compounds.

The phrase “stable or chemically feasible,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

As used herein, an “effective amount” is defined as the amount requiredto confer a therapeutic effect on the treated patient, and is typicallydetermined based on age, surface area, weight, and condition of thepatient. The interrelationship of dosages for animals and humans (basedon milligrams per meter squared of body surface) is described byFreireich et al., Cancer Chemother. Rep., 50: 219 (1966). Body surfacearea may be approximately determined from height and weight of thepatient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley,N.Y., 537 (1970). As used herein, “patient” refers to a mammal,including a human.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools or probes inbiological assays, or as therapeutic agents.

II. Pharmaceutical Compositions

It is commonly believed that efficacious insulin sensitizing compoundsmust have high PPARγ activity, and conversely, that compounds havingreduced PPARγ activity would yield reduced insulin sensitizing activity.Contrary to this belief, thiazolidinedione compounds of the presentinvention are uniquely effective in treating hypertension, diabetes, andinflammatory diseases and possess a reduced interaction with PPARγ.

Without wishing to be bound by theory, it is believed that metabolicinflammation is a central cause of the numerous key diseases includinghypertension, diabetes, and inflammatory diseases. It is furtherbelieved that thiazolidinediones of the present invention function toprevent hypertension, diabetes, and inflammatory diseases via amitochondrial mechanism. Furthermore since the dose limiting sideeffects due to PPARγ interaction are reduced in compounds of the presentinvention; especially stereoselective isomers, the compounds of formulaI are highly useful for treating hypertension, diabetes, andinflammatory diseases.

Additionally, since the thiazolidinedione analogues of the presentinvention function via a mitochondrial mechanism, the compounds offormula I are useful in treating or preventing all of the disease stateswherein metabolic inflammation is the basis of the pathology.

Furthermore since the dose limiting side effects due to PPARγinteraction are reduced in compounds of the present invention;especially steroselective isomers, the compounds of formula I when usedin combination with a glucocorticoid agonist can be used for treatinginflammatory diseases.

Generic Compositions

The present invention provides pharmaceutical compositions that areuseful for treating hypertension, diabetes, and inflammatory diseasescomprising a compound of formula I:

or a pharmaceutically acceptable salt thereof.

Each of R₁ and R₄ is independently selected from H, halo, aliphatic, andalkoxy, wherein the aliphatic and alkoxy are optionally substituted with1-3 of halo.

R₂ is halo, hydroxy, or optionally substituted aliphatic, and R′₂ is H,or R₂ and R′₂ together form oxo.

R₃ is H.

Ring A is phenyl.

In several embodiments, R₁ is H. In some embodiments, R₁ is halo, suchas F or Cl. In some embodiments, R₁ is an aliphatic optionallysubstituted with 1-3 halo. For instance, R₁ specific embodiments, R₁ is.R₁ is alkoxy. For instance, R₁ is methoxy, ethoxy, or —O-isopropyl. Instill other embodiments, R₁ is alkoxy substituted with 1-3 halo. Forinstance, R₁ is —OCHF₂ or —OCF₃. In each of the foregoing embodiments,R₁ can be is substituted at the ortho, meta, or para position on thephenyl ring. In certain embodiments, R₁ is substituted at the para ormeta position on the phenyl ring.

In several embodiments, R₄ is H. In some embodiments, R₄ is halo, suchas F or Cl. In some embodiments, R₄ is an aliphatic optionallysubstituted with 1-3 halo. For instance, R₄ specific embodiments, R₄ is.R₄ is alkoxy. For instance, R₄ is methoxy, ethoxy, or —O-isopropyl. Instill other embodiments, R₄ is alkoxy substituted with 1-3 halo. Forinstance, R₄ is —OCHF₂ or —OCF₃. In each of the foregoing embodiments,R₄ can be is substituted at the ortho, meta, or para position on thephenyl ring. In certain embodiments, R₄ is substituted at the para ormeta position on the phenyl ring. In some embodiments, R₁ and R₄ aredifferent substituents. In still other embodiments, R₁ and R₄ are thesame substituent. In some embodiments when R₁ is aliphatic, R₄ is otherthan H.

In several embodiments, each of R₁ and R₄ is independently selected fromH, halo, aliphatic, and alkoxy, wherein the aliphatic and alkoxy areoptionally substituted with 1-3 of halo, provided that when one of R₁and R₄ is H that the other is not ethyl.

In several embodiments, each of R₁ and R₄ is independently selected fromH, halo, aliphatic, and alkoxy, wherein the aliphatic and alkoxy areoptionally substituted with 1-3 of halo, provided that when one of R₁and R₄ is H that the other is not ethyl substituted at the 4 position ofthe phenyl.

In several embodiments, R₂ is hydrogen, halo, hydroxy, or an optionallysubstituted C₁₋₆ aliphatic. For example, R₂ is an optionally substitutedstraight or branched C₁₋₆ alkyl, an optionally substituted straight orbranched C₂₋₆ alkenyl, or an optionally substituted straight or branchedC₂₋₆ alkynyl. In other examples, R₂ is a C₁₋₆ aliphatic optionallysubstituted with 1-2 hydroxy or halo. In other examples, R₂ is a C₁₋₆alkyl optionally substituted with hydroxy. In several other examples, R₂is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, orhexyl, each of which is optionally substituted with hydroxy. In severaladditional examples, R₂ is methyl or ethyl, each of which is substitutedwith hydroxy.

In several embodiments, R′₂ is H. In some embodiments, R₂ and R′₂together form oxo.

In some embodiments, when one of R₁ or R₄ is H, the other is not ethyl.

In several embodiments, the composition further comprises apharmaceutically acceptable carrier.

Another aspect of the present invention provides a pharmaceuticalcomposition include a compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein R′₂ is H, and R₁,R₃, R₄ and ring A are defined above in formula I.

Exemplary compositions according to the present invention includes asingle unit dosage form having about 1 mg to about 200 mg of a compoundof formulae I or II, e.g., between about 10 mg to about 120 mg, betweenabout 10 mg to about 100 mg, or about 15 mg to about 60 mg.

Several exemplary compounds of formulae I or II are displayed in TableA, below.

TABLE A Exemplary compounds.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising a compound of formulae I or II, wherein thecompound has a PPARγ activity of 50% or less relative to the activity ofrosiglitazone when dosed to produce circulating levels greater than 3 μMor having a PPARγ activity of 10 times less than pioglitazone at thesame dosage.

Another aspect of the present invention provides a method of treatinghypertension, diabetes, and inflammatory diseases comprisingadministering a pharmaceutical composition comprising a compound offormulae I or II. The compositions of several alternative methodsfurther comprise a pharmaceutically acceptable carrier.

Another aspect of the present invention provides a method of treatinghypertension, diabetes, and inflammatory diseases comprisingadministering a pharmaceutical composition comprising a compound offormula II wherein said compound has a purity of about 70 e.e. % ormore. For example, the method treating hypertension, diabetes, andinflammatory diseases comprising administering a pharmaceuticalcomposition comprising a compound of formula I wherein the compound hasa purity of about 80% e.e. or more (e.g., 90% e.e. or more, 95% e.e. ormore, 97% e.e. or more, or 99% e.e. or more).

Pharmaceutical compositions of the present invention can also compriseone or more additional antihypertensive agents or other drugs. Oneaspect of the present invention provides pharmaceutical compositioncomprising a compound of formulae I or II and at least one diuretic,such as hydrochlorothiazide, chlorothaladone, chlorothiazide, orcombinations thereof. Other aspects provide pharmaceutical compositionsuseful for treating hypertension, diabetes, and inflammatory diseasescomprising a compound of formulae I or II and one or more agents thatlimit the activity of the renin-angiotensin system such as angiotensinconcerting enzyme inhibitors, i.e. ACE inhibitors, e.g. ramipril,captopril, enalapril, or the like, and/or angiotensin II receptorblockers, i.e. ARBs, e.g. candesartan, losartan, olmesartan, or thelike; and/or renin inhibitors. Still other aspects provide a usefulpharmaceutical composition for treating hypertension, diabetes, andinflammatory diseases comprising of a compound of formulae I or II andcompounds that limit hypertension, diabetes, and inflammatory diseasesby alternate means including β-adrenergic receptor blockers, and calciumchannel blockers, e.g., amlodipine.

This invention also provides pharmaceutical compositions that are usefulfor lowering lipids comprising compounds of formulae I or II and one ormore statin, i.e., HMG-CoA reductase inhibitor, e.g., atorvastatin,cerivastatin, fluvastatin, lovastatin, mevastatin, simvastatin,rosuvastatin, pravastatin, or any pharmaceutically acceptablecombination thereof.

Another aspect of the present invention provides a combination of acompound of formulae I or II with one or more antihypertensive agentsincluding diuretics (for example hydrochlorothiazide, chlorothaladone,chlorothiazide), angiotensive converting enzyme inhibitors, e.g., ACEinhibitors, e.g., ramipril, captopril, enalapril, combinations thereof,or the like; angiotensin II receptor blockers, i.e., ARBs, e.g.,losartan, olmesartan, telmisartan, combinations thereof, or the like;renin inhibitors; β-adrenergic receptor blockers, statins, orcombinations thereof.

III. General Synthetic Schemes

The compounds of formulae I and II may be readily synthesized fromcommercially available or known starting materials by known methods.Exemplary synthetic routes to produce compounds of formulae I or II areprovided below in Scheme 1 below.

Referring to Scheme 1, the starting material 1a is reduced to form theaniline 1b. The aniline 1b is diazotized in the presence of hydrobromicacid, acrylic acid ester, and a catalyst such as cuprous oxide toproduce the alpha-bromo acid ester 1c. The alpha-bromo acid ester 1c iscyclized with thiourea to produce racemic thiazolidinedione 1d.Compounds of formula II can be separated from the racemic mixture usingany suitable process such as HPLC.

In Scheme 2 below, R₂ is an oxo group, R₃ is hydrogen.

Referring to Scheme 2, the starting material 2a is reacted with4-hydroxybenzalde under basic conditions (e.g., aq. NaOH) to give amixture of regioisomeric alcohols 2b that were separated bychromatography. The regioisomeric alcohols 2b is reacted with2,4-thiazolidine dione using pyrrolidine as base to give compound 2c.Cobalt catalyzed reduction with sodium borohydride affords compound 2d,which is oxidized, for example, with phosphorus pentoxide in thepresence of dimethyl sulfoxide, to give the ketone 2e.

IV. Uses, Formulations, and Administration

As discussed above, the present invention provides compounds that areuseful as treatments for hypertension, diabetes, and inflammatorydiseases.

Accordingly, in another aspect of the present invention,pharmaceutically acceptable compositions are provided, wherein thesecompositions comprise any of the compounds as described herein, andoptionally comprise a pharmaceutically acceptable carrier, adjuvant orvehicle. In certain embodiments, these compositions optionally furthercomprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative or a prodrug thereof. Accordingto the present invention, a pharmaceutically acceptable derivative or aprodrug includes, but is not limited to, pharmaceutically acceptablesalts, esters, salts of such esters, or any other adduct or derivativewhich upon administration to a patient in need is capable of providing,directly or indirectly, a compound as otherwise described herein, or ametabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describes pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersible products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

In yet another aspect, the present invention provides a method oftreating hypertension, diabetes, and inflammatory diseases comprisingadministering a pharmaceutical composition comprising a compound offormulae I or II, preferably a mammal, in need thereof.

According to the invention an “effective amount” of the compound orpharmaceutically acceptable composition is that amount effective fortreating or lessening the severity of hypertension, diabetes, andinflammatory diseases.

The pharmaceutical compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity ofhypertension, diabetes, and inflammatory diseases.

The exact amount required will vary from subject to subject, dependingon the species, age, and general condition of the subject, the severityof the infection, the particular agent, its mode of administration, andthe like. The compounds of the invention are preferably formulated indosage unit form for ease of administration and uniformity of dosage.The expression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the present invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors known in the medical arts. The term “patient”, as usedherein, means an animal, for example, a mammal, and more specifically ahuman.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect. Alternatively, the compounds of the invention may beadministered orally or parenterally at dosage levels of between 10 mg/kgand about 120 mg/kg.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsulated matrices of the compound inbiodegradable polymers such as polylactide-polyglycolide. Depending uponthe ratio of compound to polymer and the nature of the particularpolymer employed, the rate of compound release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the compound in liposomes or microemulsions that arecompatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms are prepared by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas treatments for hypertension, diabetes, and inflammatory diseases.

The activity, or more importantly, reduced PPARγ activity of a compoundutilized in this invention as a treatment of hypertension, diabetes, andinflammatory diseases may be assayed according to methods describedgenerally in the art and in the examples herein.

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the present invention can be employed incombination therapies, that is, the compounds and pharmaceuticallyacceptable compositions can be administered concurrently with, prior to,or subsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, the presentinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the present invention includes an implantable device coated witha composition comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. Suitable coatingsand the general preparation of coated implantable devices are describedin U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121, each of which isincorporated by reference. The coatings are typically biocompatiblepolymeric materials such as a hydrogel polymer, polymethyldisiloxane,polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinylacetate, and mixtures thereof. The coatings may optionally be furthercovered by a suitable topcoat of fluorosilicone, polysaccarides,polyethylene glycol, phospholipids or combinations thereof to impartcontrolled release characteristics in the composition.

According to yet another embodiment, the present invention provides amethod of treating or reducing the severity of hypertension, diabetes,and inflammatory diseases.

Another aspect of the invention relates to treating hypertension,diabetes, and inflammatory diseases in a biological sample or a patient(e.g., in vitro or in vivo), which method comprises administering to thepatient, or contacting said biological sample with a pharmaceuticalcomposition comprising a compound of formulae I or II. The term“biological sample”, as used herein, includes, without limitation, cellcultures or extracts thereof; biopsied material obtained from a mammalor extracts thereof; and blood, saliva, urine, feces, semen, tears, orother body fluids or extracts thereof.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

V. Examples Example 15-[4-(2-oxo-2-phenylethoxy)benzyl]-1,3-thiazolidine-2,4-dione

Step 1. Preparation of 4-(2-hydroxy-2-phenylethoxy)benzaldehyde

To 2-(4-fluorophenyl)oxirane (6.50 g, 54.0 mmol) was added toluene (85ml), 4-hydroxybenzaldehyde (9.89 g, 81.0 mmol), PEG4000 (polyethyleneglycol, 1.15 g) and 1M NaOH (85 ml) and the stirring mixture was heatedat 78° C. overnight. After cooling to RT the reaction mixture wasextracted with EtOAc, and the organic phase was washed with brine, dried(Na₂SO₄), filtered and evaporated in vacuo. The resulting yellow oil waschromatographed on a medium silica gel column eluting with 0-10%EtOAc/DCM. Fractions containing predominantly the higher R_(f) spot werecombined and evaporated in vacuo to give 1.85 g (14%) of the titlecompound as a yellow oil. Fractions containing predominantly the lowerR_(f) spot were combined and evaporated in vacuo to give 0.64 g of theregioisomer as a colorless, viscous oil. Mixed fractions were combinedand rechromatographed eluting with 30% EtOAc/hexanes. Fractionscontaining the higher R_(f) material were combined and evaporated invacuo to give an additional 2.64 g (20%) of the title compound as acolorless oil. Fractions containing the lower R_(f) material werecombined and evaporated in vacuo to give an additional 1.82 g of theregioisomer as a colorless viscous oil.

Step 2: Preparation of5-[4-(2-hydroxy-2-phenylethoxy)benzylidene]-1,3-thiazolidine-2,4-dione

To a stirring solution of 4-[(2S)-2-hydroxy-2-phenylethoxy]benzaldehyde(2.63 g, 10.8 mmol) in absolute EtOH (75 ml) was added2,4-thiazolidinedione (1.27 g, 10.8 mmol) and piperidine (0.54 mL, 5.4mmol), and the resulting solution was heated to reflux. The reaction wasrefluxed overnight. The reaction mixture was allowed to cool to RT. Noprecipitate formed. The pH of reaction mixture was ca. 5. Acetic acid(20 drops) was added. The reaction was evaporated in vacuo. The materialwas adsorbed onto silica gel and chromatographed eluting with 30-40%EtOAc/hexanes. Fractions containing product were combined and evaporatedin vacuo to give 3.18 g (86%) of the title compound as a light yellowsolid. MS (ESI−) for C₁₈H₁₅NO₄S m/z 340.1 (M−H)⁻.

Step 3: Preparation of5-[4-(2-hydroxy-2-phenylethoxy)benzyl]-1,3-thiazolidine-2,4-dione

To a mixture of5-[4-(2-hydroxy-2-phenylethoxy)benzylidene]-1,3-thiazolidine-2,4-dione(1.50 g, 4.39 mmol) in THF (20 ml) was added H₂O (20 ml), 1M NaOH (3ml), cobalt (II) chloride hexahydrate (0.60 mg, 0.003 mmol) anddimethylglyoxime (15 mg, 0.13 mmol). A solution of sodiumtetrahydroborate (240 mg, 6.33 mmol) in 0.2M NaOH (3.6 ml) was added.The reaction mixture immediately turned dark but very soon assumed aclear yellow appearance. Acetic acid was added dropwise until thesolution turned dark (3 drops). After ca. one hour the reactionlightened. Additional NaBH₄, CoCl₂ and HOAc were added to produce a deepblue-purple color. When that color faded, more NaBH₄ was added. WhenHPLC analysis indicated that the reaction was complete, it waspartitioned between H₂O and EtOAc, and the organic phase was washed withbrine, dried (Na₂SO₄), filtered and evaporated in vacuo. The resultingfoamy solid was chromatographed, eluting with 50% EtOAc/hexanes.Fractions containing product were combined and evaporated in vacuo togive 1.15 g (76%) of the title compound as a white solid. MS (ESI−) forC₁₈H₁₇NO₄S m/z 342.1 (M−H)⁻.

Step 4: Preparation of5-[4-(2-oxo-2-phenylethoxy)benzyl]-1,3-thiazolidine-2,4-dione

To a stirring solution of5-[4-(2-hydroxy-2-phenylethoxy)benzyl]-1,3-thiazolidine-2,4-dione (1.00g, 2.91 mmol) in DCM (35 ml) was added DMSO (2 ml) and the solution wascooled to 0° C. Phosphorus pentoxide (0.83 g, 2.91 mmol) was addedfollowed by triethylamine (1.8 mL, 13.1 mmol). The reaction was allowedto slowly warm to RT. After 2 hours, the reaction mixture waspartitioned between DCM and water and the organic phase was washed withbrine, dried (Na₂SO₄), filtered and evaporated in vacuo. The resultingyellow oil was chromatographed on silica gel eluting with 25-35%EtOAc/hexanes. Fractions containing product were combined and evaporatedin vacuo to give 0.40 g (40%) of the title compound as a white solid.Trituration with ether afforded 245 mg of clean product. MS (ESI−) forC₁₈H₁₅NO₄S m/z 340.1 (M−H)⁻.

Example 2 Preparation of5-{4-[2-(4-fluorophenyl)-2-oxoethoxy]benzyl}-1,3-thiazolidine-2,4-dione

Step 1: Preparation of 4-[2-(fluorophenyl)-2-hydroxyethoxy]benzaldehyde

To a stirring solution of 2-(4-fluorophenyl)oxirane (5.60 g, 40.0 mmol)in toluene (65 ml) was added 4-hydroxybenzaldehyde (7.40 g, 61.0 mmol),1M NaOH (65 ml) and PEG4000 (polyethylene glycol, 0.85 g) and thereaction was heated at 78° C. overnight. After cooling to RT, thereaction was extracted with EtOAc (2×150 ml) and the combined extractswere washed with brine, dried (Na₂SO₄), filtered and evaporated invacuo. The resulting light brown oil was chromatographed on silica geleluting with 30-40% EtOAc/hexanes. Fractions containing the higher R_(f)spot were combined and evaporated in vacuo to give 2.38 g of theregioisomer of the product as a white solid. Fractions containing thelower R_(f) spot were combined and evaporated in vacuo to give 1.54 g(22%) of the title compound as a colorless viscous oil.

Step 2: Preparation of5-{4-[2-(4-fluorophenyl)-2-hydroxyethoxy]benzylidene}-1,3-thiazolidine-2,4-dione

To a stirring solution of the aldehyde (2.36 g, 10.8 mmol) in absoluteEtOH (75 ml) was added 2,4-thiazolidinedione (1.06 g, 9.07 mmol) andpiperidine (0.45 mL, 4.50 mmol), and the resulting solution was heatedto reflux. After refluxing overnight, the reaction was allowed to coolto RT, and then evaporated in vacuo. The residue was adsorbed ontosilica gel and chromatographed, eluting with 30-40% EtOAc/hexanes.Fractions containing product were combined and evaporated in vacuo togive 0.88 g (27%) of the title compound as a yellow solid. MS (ESI−) forC₁₈H₁₄FNO₄S m/z 358.1 (M−H)⁻.

Step 3: Preparation of5-{4-[2-(4-fluorophenyl)-2-hydroxyethoxy]benzyl}-1,3-thiazolidine-2,4-dione

To a stirring mixture of5-{4-[2-(4-fluorophenyl)-2-hydroxyethoxy]benzylidene}-1,3-thiazolidine-2,4-dione(0.87 g, 2.40 mmol) in THF/H₂O (1:1, 20 ml) was added 1M NaOH (2 ml),cobalt (II) chloride hexahydrate (0.30 g, 0.001 mmol), dimethylglyoxime(8.4 mg, 0.073 mmol), and finally sodium tetrahydroborate (0.13 g, 3.53mmol). The reaction turned a deep blue/purple color. After a short time,the dark color began to fade and HOAc was added dropwise to regeneratethe darker color. When the color faded and addition of HOAc failed toregenerate it, NaBH₄ was added to regenerate the darker color. Thereaction was left to stir at RT overnight. The reaction was partitionedbetween water and EtOAc. The organic phase was washed with brine, dried(Na₂SO₄), filtered and evaporated in vacuo. The resulting light brownoil was chromatographed, eluting with 35% EtOAc/hexanes. Fractionscontaining compound were combined and evaporated in vacuo to give 0.77 g(88%) of a light yellow solid. The yellow solid was dissolved in THF (8ml) and H₂O (8 ml), and the resulting solution was treated with CoCl₂ (asmall crystal), and 2,2′-dipyridyl (5 mg). Finally, NaBH₄ was added insmall portions until the deep blue color persisted. The reaction mixturewas partitioned between EtOAc and H₂O, and the aqueous phase wasextracted with EtOAc. The combined organic phases were washed withbrine, dried (Na₂SO₄), filtered and evaporated in vacuo. The resultingslightly tinted oil was chromatographed on a small silica gel columneluting with 25-35% EtOAc/hexanes. Fractions containing product werecombined and evaporated in vacuo to afford 527 mg (60%) of the titlecompound as a white solid. MS (ESI−) for C₁₈H₁₆FNO₄S m/z 360.1 (M−H)⁻.

Step 4: Preparation of5-{4-[2-(4-fluorophenyl)-2-oxoethoxy]benzyl}-1,3-thiazolidine-2,4-dione

To a stirring solution of5-{4-[2-(4-fluorophenyl)-2-hydroxyethoxy]benzyl}-1,3-thiazolidine-2,4-dione(0.52 g, 1.40 mmol) in DCM (15 ml) was added DMSO (0.5 ml) and thesolution was cooled to 0° C. Phosphorus pentoxide (0.41 g, 1.44 mmol)was added followed by triethylamine (0.90 mL, 6.48 mmol). The reactionwas allowed to slowly warm to RT and then stirred for 5 hours. Thereaction mixture was partitioned between DCM and H₂O, and the aqueousphase was extracted with DCM. The combined organic phases were washedwith brine, dried (Na₂SO₄), filtered and evaporated in vacuo. Theresulting white solid was chromatographed on a small silica gel columneluting with 10% EtOAc/DCM. Fractions containing product were combinedand evaporated in vacuo to give 0.25 g (48%) of the title compound as awhite solid. MS (ESI+) for C₁₈H₁₄FNO₄S m/z 359.9 (M+H)⁺. MS (ESI−) forC₁₈H₁₄FNO₄S m/z 358.0 (M−H)⁻.

Example 3 Preparation of5-{4-[2-(2-fluorophenyl)-2-oxoethoxy]benzyl}-1,3-thiazolidine-2,4-dione

Step 1: Preparation of 2-(2-fluorophenyl)oxirane

To a solution of o-fluorostyrene (5.0 g, 41.0 mmol) and acetic acid(2.33 mL, 40.9 mmol) in dioxane (33 ml) and H₂O (78 ml) at 0° C. wasadded N-bromosuccinimide (8.02 g, 45.0 mol) in three portions. Thereaction was allowed to warm to R.T and stirred overnight. Sodiumcarbonate (8.68 g, 81.9 mmol) was added in portions and then 1M NaOH(ca. 10 ml) was added and the reaction was stirred at RT overnight. Thereaction mixture was partitioned between water and EtOAc, and theaqueous phase was extracted with EtOAc. The combined organic phaseswashed with brine, dried (Na₂SO₄), filtered and evaporated in vacuo togive 5.31 g (94%) of the title compound as a slightly tinted oil whichwas used without further purification. MS (ESI+) for C₈H₇FO m/z 138.1(M+H)⁺.

Step 2: Preparation of4-[2-(2-fluorophenyl)-2-hydroxyethoxy]benzaldehyde

To a stirring solution of 2-(2-fluorophenyl)oxirane (5.30 g, 38.4 mmol)in toluene (65 ml) was added 4-hydroxybenzaldehyde (7.0 g, 58.0 mmol),1M NaOH (65 ml) and PEG4000 (polyethylene glycol, 0.85 g) and thestirring mixture was heated at 78° C. overnight. The reaction wasallowed to cool to RT and then extracted with EtOAc (2×150 ml). Thecombined extracts were washed with brine, dried (Na₂SO₄), filtered andevaporated in vacuo. The resulting light brown oil was adsorbed ontosilica gel and chromatographed, eluting with 30-40% EtOAc/hexanes. Thereare 2 major spots. Fractions containing the higher R_(f) spot werecombined and evaporated in vacuo to give 1.10 g (11%) of the titlecompound as a colorless oil. Fractions containing the lower R_(f) spotwere combined and evaporated in vacuo to give 0.67 g (7%) of theregioisomer as a colorless oil.

Step 3: Preparation of5-{4-[2-(2-fluorophenyl)-2-hydroxyethoxy]benzylidene}-1,3-thiazolidine-2,4-dione

To a stirring solution of the aldehyde (2.36 g, 10.8 mmol) in absoluteEtOH (40 ml) was added 2,4-thiazolidinedione (0.495 g, 4.23 mmol) andpiperidine (0.21 mL, 2.10 mmol), and the resulting solution was heatedto reflux. After refluxing overnight, the reaction mixture was cooled toRT and then evaporated in vacuo. The residue was dissolved in EtOAc andthis solution was washed with dilute aqueous HOAc, brine, dried(Na₂SO₄), filtered and evaporated in vacuo. The resulting yellow solidwas washed with DCM and acetone and the filtrate was evaporated invacuo. This material was adsorbed onto silica gel and chromatographedusing 10-25% EtOAc/DCM. Fractions containing compound were combined andevaporated in vacuo to give 0.51 g of the title compound as a yellowsolid. MS (ESI−) for C₁₈H₁₄FNO₄S m/z 358.0 (M−H)⁻.

Step 4: Preparation of5-{4-[2-(2-fluorophenyl)-2-hydroxyethoxy]benzyl}-1,3-thiazolidine-2,4-dione

To a stirring mixture of5-{4-[2-(2-fluorophenyl)-2-hydroxyethoxy]benzylidene}-1,3-thiazolidine-2,4-dione(0.52 g, 1.40 mmol) in THF/H₂O (1:1, 16 ml) was added 1M NaOH (2 ml),cobalt (II) chloride hexahydrate (0.2 mg, 0.0009 mmol), 2,2′-bipyridine(50.8 mg, 0.33 mmol), and finally sodium tetrahydroborate (0.11 g, 2.90mmol). The reaction turned a deep blue/purple color. After a short time,the dark color began to fade and HOAc was added dropwise to regeneratethe darker color. When the color faded and addition of HOAc failed toregenerate it, NaBH₄ was added to regenerate the darker color. Addedsmall portions of NaBH₄ and HOAc dropwise until deep blue colorpersisted. After repeating this several times, HPLC indicated that thereaction was complete despite the fact that the deep blue color hasgiven way to a light brown solution. The reaction was partitionedbetween water and EtOAc. The organic phase was washed with brine, dried(Na₂SO₄), filtered and evaporated in vacuo. The resulting light brownoil was chromatographed, eluting with 35% EtOAc/hexanes. Fractionscontaining compound were combined and evaporated in vacuo to give 0.32 gof the title compound as a white solid. MS (ESI−) for C₁₈H₁₆FNO₄S m/z360.1 (M−H)⁻.

Step 5: Preparation of5-{4-[2-(2-fluorophenyl)-2-oxoethoxy]benzyl}-1,3-thiazolidine-2,4-dione

To a stirring solution of5-{4-[2-(2-fluorophenyl)-2-hydroxyethoxy]benzyl}-1,3-thiazolidine-2,4-dione(0.29 g, 0.80 mmol) in DCM (15 ml) was added DMSO (0.5 ml) and thesolution was cooled to 0° C. Phosphorus pentoxide (0.23 g, 0.80 mmol)was added, followed by triethylamine (0.50 mL, 3.6 mmol). The reactionwas allowed to slowly warm to RT. After 3 hours, water was added and thephases were separated. The pH of the aqueous phase was adjusted to ca. 7and the aqueous phase was extracted with DCM. The combined organicphases were washed with brine, dried (Na₂SO₄), filtered and evaporatedin vacuo. The resulting white solid was chromatographed on a smallsilica gel column eluting with 10% EtOAc/DCM. Fractions containingproduct were combined and evaporated in vacuo to give 0.19 g (66%) ofthe title compound as a white solid. MS (ESI−) for C₁₈H₁₄FNO₄S m/z 358.0(M−H)⁻.

Example 4 Preparation of5-{4-[2-(3-fluorophenyl)-2-oxoethoxy]benzyl}-1,3-thiazolidine-2,4-dione

Step 1: Preparation of 2-(3-fluorophenyl)oxirane

To a solution of m-fluorostyrene (5.00 g, 41.0 mmol) and acetic acid(2.33 mL, 40.9 mmol) in dioxane (33 ml) and H₂O (78 ml) at 0° C. wasadded N-bromosuccinimide (8.02 g, 45.0 mmol) in three portions. Thereaction was allowed to warm to RT. After 4 hours, 2N NaOH (60 ml) wasadded and the reaction was left to stir at RT overnight. The reactionmixture was partitioned between water and EtOAc, and the aqueous phasewas extracted with EtOAc. The combined organic phases were washed withbrine, dried (Na₂SO₄), filtered and evaporated in vacuo to give 6.30 gof the title compound as a slightly tinted oil which was used withoutfurther purification.

Step 2: Preparation of4-[2-(3-fluorophenyl)-2-hydroxyethoxy]benzaldehyde

To a stirring solution of 2-(3-fluorophenyl)oxirane (5.60 g, 40.5 mmol)in toluene (65 ml) was added 4-hydroxybenzaldehyde (7.40 g, 61.0 mmol),1M NaOH (65 ml) and PEG4000 (polyethylene glycol, 0.85 g) and thestirring mixture was heated at 78° C. overnight. The reaction mixturewas allowed to cool to RT and then extracted with EtOAc (2×150 ml). Thecombined extracts were washed with brine, dried (Na₂SO₄), filtered andevaporated in vacuo. The resulting light brown oil was chromatographedeluting with 30-40% EtOAc/hexanes. There are 2 major spots. Fractionscontaining the higher R_(f) spot were combined and evaporated in vacuoto give 1.78 g (17%) of the title compound as a white solid. Fractionscontaining the lower R_(f) spot were combined and evaporated in vacuo togive 0.90 g (9%) of the regioisomer as a nearly colorless oil.

Step 3: Preparation of5-{4-[2-(3-fluorophenyl)-2-hydroxyethoxy]benzylidene}-1,3-thiazolidine-2,4-dione

To a stirring solution of the aldehyde (2.36 g, 10.8 mmol) in absoluteEtOH (40 ml) was added 2,4-thiazolidinedione (0.90 g, 7.69 mmol) andpiperidine (0.76 mL, 7.7 mmol), and the resulting solution was heated toreflux. After 6 hours, the reaction mixture was allowed to cool to RT.The mixture was evaporated in vacuo and the residue was dissolved inEtOAc. This solution was washed with a dilute aqueous HOAc, brine, dried(Na₂SO₄), filtered and evaporated in vacuo. The resulting yellow solidwas dissolved in MeOH/DCM adsorbed onto silica gel and chromatographedeluting with 30% EtOAc/DCM. Fractions containing compound were combinedand evaporated in vacuo to afford 2.17 g (86%) of the title compound asa yellow solid. MS (ESI−) for C₁₈H₁₄FNO₄S m/z 358.1 (M−H)⁻.

Step 4: Preparation of5-{4-[2-(3-fluorophenyl)-2-hydroxyethoxy]benzyl}-1,3-thiazolidine-2,4-dione

5-{4-[2-(3-fluorophenyl)-2-hydroxyethoxy]benzylidene}-1,3-thiazolidine-2,4-dione(1.00 g, 2.78 mmol) was suspended in THF (15 ml) and H₂O (10 ml). Tothis solution was added a small crystal of cobalt chloride followed by2,2′-bipyridine (98 mg, 0.63 mmol). NaBH₄ was added in portions untilblue color persisted. The color gradually faded and was regeneratedrepeatedly by small additions of borohydride and HOAc. When HPLCanalysis indicated that the reaction was complete, the reaction mixturewas partitioned between EtOAc and H₂O. HOAc was added until the pH ofthe aqueous phase was ca. 6. The aqueous phase was extracted with EtOAc.The combined organic phases were washed with brine, dried (Na₂SO₄),filtered and evaporated in vacuo. The residue was chromatographed on asmall silica gel column eluting with 20% EtOAc/DCM. Fractions containingproduct were combined and evaporated in vacuo to give 0.72 g (72%) ofthe title compound as a white solid. This material was rechromatographedon a small silica column eluting with 10-20% EtOAc/DCM. MS (ESI−) forC₁₈H₁₆FNO₄S m/z 360.1 (M−H)⁻.

Step 5: Preparation of5-{4-[2-(3-fluorophenyl)-2-oxoethoxy]benzyl}-1,3-thiazolidine-2,4-dione

To a stirring solution of5-{4-[2-(3-fluorophenyl)-2-hydroxyethoxy]benzyl}-1,3-thiazolidine-2,4-dione(0.62 g, 1.70 mmol) in DCM (15 ml) was added DMSO (0.5 ml) and thesolution was cooled to 0° C. Added phosphorus pentoxide (0.49 g, 1.72mmol) followed by triethylamine (1.1 mL, 7.72 mmol). The reactionmixture was allowed to slowly warm to RT. After 2 hours, HPLC shows thatthe reaction was complete. Added water and separated phases. The pH ofthe aqueous phase was adjusted to ca. 7 with 2M NaOH and the aqueousphase was then extracted with EtOAc. The combined extracts were washedwith brine, dried (Na₂SO₄), filtered and evaporated in vacuo. Theresulting white solid was chromatographed on a small silica gel columneluting with 10% EtOAc/DCM. Fractions containing product were combinedand evaporated in vacuo to give 0.25 g (40%) of the title compound as awhite solid. MS (ESI−) for C₁₈H₁₄FNO₄S m/z 358.0 (M−H)⁻.

Example 5 Preparation of5-{4-[2-(3-methoxyphenyl)-2-oxoethoxy]benzyl}-1,3-thiazolidine-2,4-dione

Step 1: 2-(3-methoxyphenyl)oxirane

To a solution of 3-vinylanisole (5.0 g, 37.0 mmol) and acetic acid (2.1mL, 37.0 mmol) in dioxane (33 ml) and H₂O (78 ml) at 0° C. was addedN-bromosuccinimide (7.30 g, 41.0 mmol) in three portions. The reactionwas allowed to warm to R.T. and then 2M NaOH (50 ml) was added. Thereaction was left to stir at RT overnight. The reaction mixture was thenpartitioned between water and EtOAc, and the aqueous phase was extractedwith EtOAc. The combined organic phases washed with brine, dried(Na₂SO₄), filtered and evaporated in vacuo to give 5.60 g (100%) of thetitle compound as a slightly tinted oil.

Step 2: 4-[2-hydroxy-2-(3-methoxyphenyl)ethoxy]benzaldehyde

To a stirring solution of 2-(3-methoxyphenyl)oxirane (5.60 g, 37.0 mmol)in toluene (65 ml) was added 4-hydroxybenzaldehyde (6.80 g, 5.60 mmol),1M NaOH (65 ml) and PEG4000 (polyethylene glycol, 0.85 g) and thestirring mixture was heated at 78° C. overnight. The reaction mixturewas allowed to cool to RT and extracted with EtOAc (2×150 ml). Thecombined extracts were washed with brine, dried (Na₂SO₄), filtered andevaporated in vacuo. The resulting light brown oil was chromatographed,eluting with 30-40% EtOAc/hexanes. Fractions containing the higher R_(f)spot were combined and evaporated in vacuo to give 1.86 g (18%) of thetitle compound as a clear colorless oil. Fractions containing the lowerR_(f) spot were combined and evaporated in vacuo to give 0.90 g (9%) theregioisomer as a nearly colorless oil.

Step 3:5-{4-[2-hydroxy-2-(3-methoxyphenyl)ethoxy]benzylidene}-1,3-thiazolidine-2,4-dione

To a stirring solution of4-[2-hydroxy-2-(3-methoxyphenyl)ethoxy]benzaldehyde (1.76 g, 6.46 mmol)in absolute EtOH (50 ml) was added 2,4-thiazolidinedione (0.83 g, 7.11mmol) and piperidine (0.70 mL, 7.11 mmol), and the resulting solutionwas heated to reflux. The reaction was refluxed overnight and thenevaporated in vacuo. The residue was dissolved in EtOAc and thissolution was washed with water (pH adjusted to ca. 5-6 with HOAc),brine, dried (Na₂SO₄), filtered and adsorbed onto silica gel. Afterchromatography with 20-30% EtOAc/DCM, the fractions containing compoundwere combined and evaporated in vacuo to give 1.38 g (58%) of the titlecompound as a yellow solid. MS (ESI−) for C₁₉H₁₇NO₅S m/z 370.1 (M−H)⁻.

Step 4:5-{4-[2-hydroxy-2-(3-methoxyphenyl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione

5-{4-[2-hydroxy-2-(3-methoxyphenyl)ethoxy]benzylidene}-1,3-thiazolidine-2,4-dione(1.15 g, 3.10 mmol) was dissolved in THF (15 ml). Added H₂O (15 ml) andsufficient THF to give a clear solution. A small crystal of cobaltchloride was added, followed by 2,2′-bipyridine (109 mg, 0.70 mmol).NaBH₄ was added in portions until the blue color persisted. The colorgradually faded, but was regenerated repeatedly by small additions ofborohydride and HOAc. When HPLC indicated that the reaction was completethe reaction mixture was partitioned between EtOAc and H₂O. HOAc wasadded until the pH of the aqueous phase was ca. 6, and then the aqueousphase was extracted with EtOAc. The combined organic phases were washedwith brine, dried (Na₂SO₄), filtered and evaporated in vacuo. Theresidue was chromatographed on a small silica gel column eluting with20% EtOAc/DCM. Fractions containing product were combined and evaporatedin vacuo to give 0.82 g (74%) of the title compound as a white solid. MS(ESI−) for C₁₉H₁₉NO₅S m/z 372.0 (M−H)⁻.

Step 5: Preparation of5-{4-[2-(3-methoxyphenyl)-2-oxoethoxy]benzyl}-1,3-thiazolidine-2,4-dione

To a stirring solution of5-{4-[2-hydroxy-2-(3-methoxyphenyl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione(0.62 g, 1.7 mmol) in DCM (15 ml) was added DMSO (0.5 ml) and thesolution was cooled to 0° C. Added phosphorus pentoxide (0.52 g, 1.8mmol) followed by triethylamine (1.2 mL, 8.3 mmol). The reaction wasallowed to slowly warm to RT. After 2 hours water was added and thephases were separated. The pH of the aqueous phase was adjusted to ca. 7with 2M NaOH. The aqueous phase was extracted with EtOAc. The combinedextracts were washed with brine, dried (Na₂SO₄), filtered and evaporatedin vacuo. The resulting white solid was chromatographed on a smallsilica gel column eluting with 10% EtOAc/DCM. Fractions containingproduct were combined and evaporated in vacuo to give 0.33 g (54%) ofthe title compound as a white solid. MS (ESI+) for C₁₉H₁₇NO₅S m/z 372.0(M+H)⁺. MS (ESI−) for C₁₉H₁₇NO₅S m/z 370.1 (M−H)⁻.

Example 6 Preparation of5-{4-[2-(2-methoxyphenyl)-2-oxoethoxy]benzyl}-1,3-thiazolidine-2,4-dione

Step 1: Preparation of 2-(2-methoxyphenyl)oxirane

To a solution of 2-vinyl anisole (5.0 g, 0.037 mol) and acetic acid (2.1mL, 37 mmol) in dioxane (33 ml) and H₂O (78 ml) at 0° C. was addedN-bromosuccinimide (7.30 g, 40.1 mmol) in three portions. The reactionwas allowed to warm to R.T. and after 1 hour, 2M NaOH (50 ml) was added.The reaction was left to stir at RT overnight. The reaction mixture waspartitioned between water and EtOAc, and the aqueous phase was extractedwith EtOAc. The combined organic phases were washed with brine, dried(Na₂SO₄), filtered and evaporated in vacuo to give 7.56 g slightlytinted oil. This was dissolved in dioxane, 2N NaOH was added and thereaction was stirred at RT overnight. Repeated aqueous work-up gave 5.60g of the title compound as a nearly colorless oil.

Step 2: Preparation of4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy]benzaldehyde

To a stirring solution of 2-(2-methoxyphenyl)oxirane (5.60 g, 37.3 mmol)in toluene (65 ml) was added 4-hydroxybenzaldehyde (6.80 g, 56.0 mmol),1M NaOH (65 ml) and PEG4000 (polyethylene glycol, 0.85 g) and thestirring mixture was heated at 78° C. overnight. The reaction wasallowed to cool to RT and it was then extracted with EtOAc (2×150 ml).The combined extracts were washed with brine, dried (Na₂SO₄), filteredand evaporated in vacuo. The resulting light oil was adsorbed ontosilica gel and chromatographed eluting with 30-40% EtOAc/hexanes. Thereare 2 major spots. Fractions containing the higher Rf spot were combinedand evaporated in vacuo to give 1.71 g (17%) the regioisomer as a brownoil. Fractions containing the lower R_(f) spot were combined andevaporated in vacuo to give 2.05 g (20%) of the title compound as ayellow solid.

Step 3: Preparation of(5Z)-5-{4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy]benzylidene}-1,3-thiazolidine-2,4-dione

To a stirring solution of4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy]benzaldehyde (1.71 g, 6.28 mmol)in absolute EtOH (50 ml) was added 2,4-thiazolidinedione (0.81 g, 6.91mmol) and piperidine (0.68 mL, 6.9 mmol), and the resulting solution washeated to reflux. The reaction was refluxed overnight and thenevaporated in vacuo. The residue was dissolved in EtOAc and thissolution was washed with aqueous HOAc (pH 5-6), brine, dried (Na₂SO₄),filtered and evaporated in vacuo. The residue was adsorbed onto silicagel and chromatographed on silica gel eluting with 20-40% EtOAc/DCM.Fractions containing product were combined and evaporated in vacuo togive 1.87 g (80%) of the title compound as a light yellow solid. MS(ESI−) for C₁₉H₁₇NO₅S m/z 370.1 (M−H)⁻.

Step 4:5-{4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione

(5Z)-5-{4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy]benzylidene}-1,3-thiazolidine-2,4-dione(1.00 g, 2.69 mmol) was dissolved in THF (20 ml). Water (20 ml) wasadded and then sufficient additional THF was added to give a clearsolution. A small crystal of cobalt chloride was added followed by2,2′-bipyridine (95 mg, 0.61 mmol). The reaction mixture was cooled to0° C. NaBH₄ was added in portions until the blue color persisted. Thecolor gradually faded and was regenerated repeatedly by small additionsof borohydride and HOAc. When HPLC indicated that the reaction wascomplete the reaction mixture was partitioned between EtOAc and H₂O.HOAc was added until the pH of the aqueous phase was ca. 6, and theaqueous phase was extracted with EtOAc. The combined organic phases werewashed with brine, dried (Na₂SO₄), filtered and evaporated in vacuo. Theresidue was chromatographed on a small silica gel column eluting with20% EtOAc/DCM. Fractions containing product were combined and evaporatedin vacuo to give 0.63 g (63%) of the title compound as a white solid. MS(ESI−) for C₁₉H₁₉NO₅S m/z 372.1 (M−H)⁻.

Step 5: Preparation of5-{4-[2-(2-methoxyphenyl)-2-oxoethoxy]benzyl}-1,3-thiazolidine-2,4-dione

To a stirring solution of phosphorus pentoxide (0.30 g, 1.10 mmol) inDCM (8 ml) at 0° C. was added a solution of5-{4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione(0.20 g, 0.54 mmol) in DCM (8 ml) followed by dimethyl sulfoxide (0.20mL, 2.80 mmol). After stirring for 15 minutes, N,N-diisopropylethylamine(0.28 mL, 1.60 mmol) was added. After 45 minutes, the reaction mixturewas cast into cold saturated NaHCO₃ and extracted with EtOAc (×2). Thecombined extracts were washed with brine, dried (Na₂SO₄), filtered andevaporated in vacuo. The residue was chromatographed on a small silicagel column eluting with 0-10% EtOAc/DCM. Fractions containing productwere combined and evaporated in vacuo to give 175 mg (88%) of the titlecompound as a light yellow solid. MS (ESI−) for C₁₉H₁₇NO₅S m/z 370.1(M−H)⁻.

Example 7 Preparation of5-{4-[2-(3-chlorophenyl)-2-oxoethoxy]benzyl}-1,3-thiazolidine-2,4-dione

Step 1: 2-(3-chlorophenyl)oxirane

To a solution of m-chlorostyrene (5.70 g, 41.0 mmol) and acetic acid(2.33 mL, 40.9 mmol) in dioxane (33 ml) and H₂O (78 ml) at 0° C. wasadded N-bromosuccinimide (8.02 g, 45.0 mmol) in three portions. Thereaction was allowed to warm to R.T. After 4 hours, 2N NaOH (60 ml) wasadded and the reaction was allowed to stir at RT overnight. The reactionmixture was partitioned between water and EtOAc, and the aqueous phasewas extracted with EtOAc. The combined organic phases were washed withbrine, dried (Na₂SO₄), filtered and evaporated in vacuo to give 6.20 gof a slightly tinted oil which was used without further purification.

Step 2: 4-[2-(3-chlorophenyl)-2-hydroxyethoxy]benzaldehyde

To a stirring solution of 2-(3-chlorophenyl)oxirane (6.20 g, 40.0 mmol)in toluene (65 ml) was added 4-hydroxybenzaldehyde (7.30 g, 60.0 mmol),1M NaOH (65 ml) and PEG4000 (polyethylene glycol, 0.85 g) and thestirring mixture was heated at 78° C. for three hours. The reaction wasallowed to cool to RT and then extracted with EtOAc (2×150 ml). Thecombined extracts were washed with brine, dried (Na₂SO₄), filtered andevaporated in vacuo. The resulting light brown oil was adsorbed ontosilica gel and chromatographed eluting with 25-40% EtOAc/hexanes. Thereare 2 major spots. Fractions containing the higher Rf spot were combinedand evaporated in vacuo to give 1.08 g (10%) of the desired product as acolorless oil. Fractions containing the lower Rf spot were combined andevaporated in vacuo to give 0.95 g (8%) of the regioisomer as acolorless oil, 44B. Some starting epoxide (2.85 g) was also recovered.

Step 3:5-{4-[2-(3-chlorophenyl)-2-hydroxyethoxy]benzylidene}-1,3-thiazolidine-2,4-dione

To a stirring solution of4-[2-(3-chlorophenyl)-2-hydroxyethoxy]benzaldehyde (1.08 g, 3.90 mmol)in absolute EtOH (50 ml) was added 2,4-thiazolidinedione (0.50 g, 4.29mmol) and piperidine (0.42 mL, 4.3 mmol), and the resulting solution washeated to reflux and then stirred overnight at room temperature. Thereaction mixture was evaporated in vacuo and the residue was dissolvedin EtOAc. This solution was washed with aqueous HOAc (pH 5-6), brine,dried (Na₂SO₄), filtered and evaporated in vacuo. The residue wasadsorbed onto silica gel and chromatographed eluting with 10-20%EtOAc/DCM. Fractions containing product were combined and evaporated invacuo to give 1.31 g (89%) of the product as a light yellow solid. MS(ESI+) for C₁₈H₁₄ClNO₄S m/z 375.0 (M+H)⁺. MS (ESI−) for C₁₈H₁₄ClNO₄S m/z374.1 (M−H)⁻.

Step 4:5-{4-[2-(3-chlorophenyl)-2-hydroxyethoxy]benzyl}-1,3-thiazolidine-2,4-dione

5-{4-[2-(3-chlorophenyl)-2-hydroxyethoxy]benzylidene}-1,3-thiazolidine-2,4-dione(0.74 g, 2.00 mmol) was dissolved in THF (20 ml). Water (20 ml) wasadded and then more THF was added until all solids dissolved. A smallcrystal of cobalt chloride was added, followed by 2,2′-bipyridine (69mg, 0.44 mmol). The reaction mixture was cooled to 0° C. NaBH₄ was addedin portions until the blue color persisted. The color gradually fadedand was regenerated repeatedly by small additions of borohydride andHOAc. When HPLC indicated that the reaction was complete, the reactionmixture was partitioned between EtOAc and H₂O. HOAc was added until thepH of the aqueous phase was ca. 6, and then the aqueous phase wasextracted with EtOAc. The combined organic phases were washed withbrine, dried (Na₂SO₄), filtered and evaporated in vacuo. The residue waschromatographed on a small silica gel column eluting with 0-10%EtOAc/DCM. Fractions containing product were combined and evaporated invacuo to give 0.44 g (59%) of a sticky yellow solid. MS (ESI−) forC₁₈H₁₆ClNO₄S m/z 376.1 (M−H)⁻.

Step 5: Preparation of5-{4-[2-(3-chlorophenyl)-2-oxoethoxy]benzyl}-1,3-thiazolidine-2,4-dione

To a stirring solution of phosphorus pentoxide (0.38 g, 1.30 mmol) inDCM (8 ml) at 0° C. was added a solution of5-{4-[2-(3-chlorophenyl)-2-hydroxyethoxy]benzyl}-1,3-thiazolidine-2,4-dione(0.25 g, 0.66 mmol) in DCM (8 ml) followed by dimethyl sulfoxide (0.23mL, 3.30 mml). After stirring for 15 minutes N,N-diisopropylethylamine(0.34 mL, 2.00 mmol) was added. After 45 minutes the reaction was pouredinto cold sat'd NaHCO₃ and the mixture was extracted with EtOAc (×2).The combined extracts were washed with brine, dried (Na₂SO₄), filteredand evaporated in vacuo. The residue was chromatographed on a smallsilica gel column eluting with 0-15% EtOAc/DCM. Fractions containingproduct were combined and evaporated in vacuo to give 117 mg (47%) of awhite solid. MS (ESI−) for C₁₈H₁₄ClNO₄S m/z 374.1 (M−H)⁻.

Example 8 Preparation of5-{4-[2-(2-chlorophenyl)-2-oxoethoxy]benzyl}-1,3-thiazolidine-2,4-dione

The title compound can be prepared as described in Example 7 usingappropriate starting materials, such as 2-(2-chlorophenyl)oxirane.

Example 9 Preparation of5-{4-[2-(4-methoxyphenyl)-2-oxoethoxy]benzyl}-1,3-thiazolidine-2,4-dione

The title compound was prepared as described in Examples 5 and 6 usingappropriate starting materials, such as 2-(4-methoxyphenyl)oxirane. MS(ESI−) for C₁₉H₁₇NO₅S 370.2 m/z (M−1).

Example 10 Assays

Assays for Measuring Reduced PPARγ Receptor Activation

Whereas activation of the PPARγ receptor is generally believed to be aselection criteria to select for molecules that may have anti-diabeticand insulin sensitizing pharmacology, this invention finds thatactivation of this receptor should be a negative selection criterion.Molecules will be chosen from this chemical space because they havereduced, not just selective, activation of PPARγ. The optimal compoundshave at least a 10-fold reduced potency as compared to pioglitazone andless than 50% of the full activation produced by rosiglitazone in assaysconducted in vitro for transactivation of the PPARγreceptor. The assaysare conducted by first evaluation of the direct interactions of themolecules with the ligand binding domain of PPARγ. This can be performedwith a commercial interaction kit that measures the direct interactionby florescence using rosiglitazone as a positive control. Further assayscan be conducted in a manner similar to that described by Lehmann et al.[Lehmann J M, Moore L B, Smith-Oliver T A: An AntidiabeticThiazolidinedione is a High Affinity Ligand for PeroxisomeProliferator-activated Receptor (PPAR) J. Biol. Chem. (1995) 270: 12953]but will use luciferase as a reporter as in Vosper et al. [Vosper, H.,Khoudoli, G A, Palmer, C N (2003) The peroxisome proliferators activatedreceptor d is required for the differentiation of THP-1 moncytic cellsby phorbol ester. Nuclear Receptor 1:9]. Compound stocks will bedissolved in DMSO and added to the cell cultures at final concentrationsof 0.1 to 100 μM and the relative activation will be calculated asinduction of the reporter gene (luciferase) as corrected for by theexpression of the control plasmid (coding for galactosidase).Pioglitazone and rosiglitazone will be used as reference compounds asdescribed above.

In addition to showing the reduced activation of the PPARγ receptor invitro, the compounds will not produce significant activation of thereceptor in animals. Compounds dosed to full effect for insulinsensitizing actions in vivo (see below) will be not increase activationof PPARγ in the liver as measured by the expression of a P2, a biomarkerfor ectopic adipogenesis in the liver [Matsusue K, Haluzik M, Lambert G,Yim S-H, Oksana Gavrilova O, Ward J M, Brewer B, Reitman M L, Gonzalez FJ. (2003) Liver-specific disruption of PPAR in leptin-deficient miceimproves fatty liver but aggravates diabetic phenotypes. J. Clin.Invest.; 111: 737] in contrast to pioglitazone and rosiglitazone, whichdo increase a P2 expression under these conditions.

The insulin sensitizing and antidiabetic pharmacology are measured inthe KKA^(Y) mice as previously reported [Hofmann, C., Lomez, K., andColca, J. R. (1991). Glucose transport deficiency corrected by treatmentwith the oral anti-hyperglycemic agent Pioglitazone. Endocrinology,129:1915-1925.] Compounds are formulated in 1% sodium carboxymethylcellulose, and 0.01% tween 20 and dosed daily by oral gavage.After 4 days of once daily treatment, treatment blood samples are takenfrom the retro-orbital sinus and analyzed for glucose, triglycerides,and insulin as described in Hofmann et al. Doses of compounds thatproduce at least 80% of the maximum lowering of glucose, triglycerides,and insulin will not significantly increase the expression of a P2 inthe liver of these mice.

Measuring PPARγ Receptor Activation

The ability of several exemplary compounds of the present invention tobind to PPARγ was measured using a commercial binding assay (InvitrogenCorporation, Carlsbad, Calif.) that measures the test compounds abilityto bind with PPAR-LBD/Fluormone PPAR Green complex. These assays wereperformed on three occasions with each assay using four separate wells(quadruplicate) at each concentration of tested compound. The data aremean and SEM of the values obtained from the three experiments.Rosiglitazone was used as the positive control in each experiment.Compounds were added at the concentrations shown, which range from0.1-100 micromolar.

Glucose, Insulin, and Triglyceride in Diabetic KKAy Mice Treated withExemplary Compounds of the Present Invention.

The insulin sensitizing and antidiabetic pharmacology are measured inthe KKA^(Y) mice as previously reported [Hofmann, C., Lornez, K., andColca, J. R. (1991). Glucose transport deficiency corrected by treatmentwith the oral anti-hyperglycemic agent Pioglitazone. Endocrinology,129:1915-1925.]. Compounds are formulated in 1% sodium carboxymethylcellulose, and 0.01% tween 20 and dosed daily by oral gavage.After 4 days of once daily treatment, blood samples are taken from theretro-orbital sinus and analyzed for glucose, triglycerides, and insulinas described in Hofmann et al. Doses of compounds that produce at least80% of the maximum lowering of glucose, triglycerides, and insulin willnot significantly increase the expression of a P2 in the liver of thesemice.

Compounds were formulated by suspension and orally dosed to KKAy mice at93 mg/kg for 4 days. The compounds were first dissolved in DMSO and thenplaced into aqueous suspension containing 7-10% DMSO, 1% sodiummethylcarboxycellulose, and 0.01% Tween 20. On the fifth day, the micewere fasted and blood samples were obtained approximately 18 hours afterthe last dose. The parameters were measured by standard assay methods.Data are mean and SEM N=6-12 mice.

TABLE B Assay Results % Rosiglitazone binding to PPARg KKAy Mouse (100uM vs. 10 uM) Glucose Insulin TG Glucose (Mean/SD) (Mean/SD) (Mean/SD)(Mean/SD) Vehicle 518 24 284 A 59 5 36 Ex. 1 0.71 0.13 0.56 36.5 0.030.02 0.05 2.4 Ex. 2 0.61 0.10 0.45 63.7 0.02 0.02 0.02 12.2 Ex. 3 0.640.20 0.62 97.9 0.02 0.07 0.04 4.0 Ex. 4 0.62 0.24 0.46 64.8 0.05 0.050.07 17.5 Ex. 5 0.56 0.22 0.41 13.2 0.05 0.03 0.06 0.6 Ex. 6 0.75 1.200.80 76.2 0.04 0.27 0.11 5.6 Ex. 7 0.54 0.59 0.43 74.4 0.03 0.33 0.041.4 Ex. 8 1.05 0.47 0.97 — 0.03 0.04 0.10 Ex. 9 1.00 0.76 0.90 37.2 0.030.21 0.06 5.0

Compounds from examples 1, 2, 3, 4 and 5 exhibited a plasma insulinlevel of less than about 5 ng/ml and example 6 exhibited a plasmainsulin level between about 15 and 20 ng/ml; examples 1, 2, 3, 4, and 5exhibited a plasma triglyceride level of between about 100 and 200 mg/dland example 6 exhibited a plasma triglyceride level between about 300and 400 mg/dl; examples 1, 2, 3, 4, and 5 exhibited a plasma glucloselevel of between about 350 and 425 mg/dl and example 6 exhibited aplasma glucose level between about 450 and 525 mg/dl.

The PPARγ-sparing compounds of this invention will be more effective forthe treatment of diseases caused by metabolic inflammation such asdiabetes and metabolic syndrome by limiting the side effectsattributable to direct and partial activation of nuclear transcriptionfactors.

Because the compounds of the present invention exhibit reduced PPARγactivation, it is anticipated that these compounds are suitable for usein combination with other compounds having antidiabetic activity, suchas metformin, DDP-4 inhibitors, or other antidiabetic agents thatfunction by differing mechanisms to augment the actions or secretions ofGLP1 or insulin. Specifically because of the reduced PPARγ interaction,these compounds will also be useful for treating dyslipidemia associatedwith metabolic inflammatory diseases combining particularly well withlipid lowering statins such as atorvastatin or the like. It is alsoanticipated that the combination of a compound of formula I and otherantidiabetic compounds will be more effective in treating diabetes thancombinations with PPAR-activating compounds as they will avoid sideeffects associated with PPARγ activation that may include volumeexpansion, edema, and bone loss.

Other Embodiments

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

1. A pharmaceutical composition comprising the compound

and a pharmaceutically acceptable carrier.
 2. The pharmaceuticalcomposition of claim 1, further comprising a diuretic selected fromhydrochlorothiazide, chlorothaladone, chlorothiazide, or any combinationthereof; a statin selected from atorvastatin, cerivastatin, fluvastatin,lovastatin, mevastatin, simvastatin, rosuvastatin, pravastatin, or anycombination thereof; an angiotension II receptor blocker selected fromlosartan, olmesartan, telmisartan, or any combination thereof; an ACEinhibitor selected from ramipril, captopril, enalapril, or anycombination thereof; calcium channel blocker selected from amlodipine;or combination thereof.
 3. The pharmaceutical composition of claim 1,further comprising a glucocorticoid agonist selected from cortisone,hydrocortisone, predisone, prednisolone, methylprednisolone,betamethasone, triamcinolone, or any combination thereof.
 4. A compoundselected from:5-(4-(2-(3-methoxyphenyl)-2-oxoethoxy)benzyl)thiazolidine-2,4-dione.